TEL is a new member of the Ets family of transcription factors which contribute to the pathogenesis of a wide variety of human hematopoietic malignancies. TEL is particularly remarkable because different chromosomal translocations result in the aberrant expression of different domains of the protein: either the DNA-binding Ets rearranged genes in human leukemia, little is known about the function of the normal TEL protein. In particular, the function of the HLH domain, highly conserved among Ets proteins, is entirely unknown. Our preliminary work, however, suggests that the TEL HLH domain encode a previously unrecognized self-association motif. Given the important role of TEL in hematopoietic malignancy, it is likely that TEL also plays a role in normal hematopoiesis. The overall goal of this proposal, therefore, is to take a first step toward the characterization of the biologic functions of the normal TEL protein, with an eye toward using these insights to understand the pathogenesis of TEL-associated leukemia. The Specific Aims of this proposal are: To characterize TEL DNA-binding and trans-activation properties To characterize TEL protein-protein interactions and phosphorylation To examine the role of TEL in hematopoietic development and neoplasia in vivo It is anticipated that the elucidation of TEL structure/function relationships will promote a better understanding of both the mechanism of TEL-mediated transformation and the role of Ets proteins in hematopoiesis.